Process for preparing brivaracetam

Abstract

The present invention discloses a novel process for preparing Brivaracetam, belonging to the field of chemical synthesis. According to the process, optically pure (R)-4-n-propyl-dihydrofuran-2(3H)-one was used as a starting material, after the steps of ring opening, halogenation, condensation, ring-closing, etc, high-purity Brivaracetam is given. The preparation process has the advantages of easy availability of raw materials, low price, high yield, high optical purity of product, simple reaction conditions and simple operations.

1 . A novel process for preparing Brivaracetam, comprising the following steps:
 1) providing a compound (R)-3-bromomethylhexanoyl halide of formula III,   2) carrying out a condensation reaction of the compound of formula III with (S)-2-aminobutyramide in the presence of an acid-binding agent, to give a compound of formula IV, i.e. (R)-3-bromomethyl-hexanoic acid-[(S)-1-carbamoyl-propyl]-amide,   3) carrying out a substitution reaction of the compound of formula IV in the presence of an alkaline reagent, and a ring-closing reaction, to give the compound of formula I;   
       
         
           
           
               
               
           
         
         where, X is selected from chlorine or bromine. 
       
     
     
         2 . The preparation process according to  claim 1 , wherein the acid-binding agent is an organic base, and the solvent for the condensation reaction is an aprotic solvent. 
     
     
         3 . The preparation process according to  claim 2 , wherein the acid-binding agent is one or more from triethylamine, pyridine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo [2.2.2]octane, N,N-dimethylaminopyridine, N,N-dimethyl-p-toluidine, and the solvents for the condensation reaction are any one or more from dichloromethane, chloroform, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, ethyl acetate, isopropyl acetate, tert-butyl acetate, methyl acetate, ethyl formate. 
     
     
         4 . The preparation process according to  claim 3 , wherein the acid-binding agent is triethylamine or pyridine, and the solvent for condensation reaction is tetrahydrofuran. 
     
     
         5 . The preparation process according to  claim 1 , wherein the molar ratio of the compound of formula III to the acid-binding agent is 1:1-10, the molar ratio of the compound of formula III to (S)-2-aminobutanamide is 1:0.5-5, and the temperature of the condensation reaction is −10 to 50° C. 
     
     
         6 . The preparation process according to  claim 5 , wherein the molar ratio of the compound of formula III to the acid-binding agent is 1:1-3, the molar ratio of the compound of formula III to (S)-2-aminobutanamide is 1:1.0-2.0, and the temperature of the reaction is −10 to 10° C. 
     
     
         7 . The preparation process according to  claim 1 , wherein the alkaline reagent is lithium diisopropylamide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, potassium t-butoxide, lithium tert-butoxide, and the solvent for the substitution reaction is an aprotic solvent. 
     
     
         8 . The preparation process according to  claim 7 , wherein the solvent for the substitution reaction is dichloromethane, chloroform, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether or 1, 4-dioxane. 
     
     
         9 . The preparation process according to  claim 8 , wherein alkaline reagent is lithium diisopropylamide, lithium bistrimethylsilylamide and the solvent for the substitution reaction is tetrahydrofuran or methyltetrahydrofuran. 
     
     
         10 . The preparation process according to  claim 7 , the molar ratio of the compound of formula IV to the alkaline reagent is 1:0.9-2.0, and the temperature of the substitution reaction is −50 to 10° C. 
     
     
         11 . The preparation process according to  claim 10 , wherein the molar ratio of the compound of formula IV to the alkaline reagent is 1:1.0-1.5, and the temperature of the substitution reaction is −30 to −5° C. 
     
     
         12 . The preparation process according to  claim 1 , wherein the compound of formula III is prepared by the following steps:
 (A) the compound of formula V reacts with trimethylbromosilane under the catalysis of anhydrous zinc chloride to give a compound of the formula II, i.e. (R)-3-bromomethylhexanoic acid,   (B) the compound of formula II reacts with a halogenated agent, to give a compound of formula III;   (V), (II), (III).   
     
     
         13 . The preparation process according to  claim 12 , wherein the reaction in the step (A) is carried out in the absence of a solvent or in the presence of an aprotic solvent. 
     
     
         14 . The preparation process according to  claim 13 , wherein the aprotic solvent is any one or more of dichloromethane, chloroform, toluene, xylene, n-heptane, n-hexane, petroleum ether, cyclohexane, cyclopentane, n-pentane and ethyl acetate. 
     
     
         15 . The preparation process according to  claim 14 , wherein the aprotic solvent is toluene or n-heptane. 
     
     
         16 . The preparation process according to  claim 12 , wherein the molar ratio of the compound of the formula V to trimethylbromosilane is 1:1-10, and the molar ratio of the compound of the formula V to anhydrous zinc chloride is 1:0.1-3, the reaction temperature of the step (A) is 20 to 90° C. and the reaction time is 0.5 to 5 hours. 
     
     
         17 . The preparation process according to  claim 16 , wherein molar ratio of the compound of the formula V to trimethylbromosilane is 1:2-5, and the molar ratio of the compound of the formula V to anhydrous zinc chloride is 1:0.5-1, the reaction temperature of the step (A) is 60 to 80° C. and the reaction time is 0.5 to 2.0 hours. 
     
     
         18 . The preparation process according to  claim 12 , wherein the reaction in the step (B) is carried out in the absence of a solvent or in the presence of an aprotic solvent. 
     
     
         19 . The preparation process according to  claim 18 , wherein the aprotic solvent is any one or more of dichloromethane, chloroform, toluene, xylene, n-heptane, n-hexane, petroleum ether, cyclohexane, cyclopentane, n-pentane, and ethyl acetate, and the halogenated agent is one of thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, thionyl bromide, oxalyl bromide and phosphorus tribromide. 
     
     
         20 . The preparation process according to  claim 19 , wherein the aprotic solvent is dichloromethane or toluene, and the halogenated agent is thionyl chloride or oxalyl chloride. 
     
     
         21 . The preparation process according to  claim 18 , wherein the molar ratio of the compound of formula II to the halogenated agent is 1:1-10, and the reaction temperature of the step (B) is −10 to 50° C. 
     
     
         22 . The preparation process according to  claim 21 , wherein the molar ratio of the compound of formula II to the halogenated agent is 1:1-4, and the reaction temperature of the step (B) is 0 to 30° C.